Pharmaceutical Standards for Artemisinin and its ... · its derivatives Requirements for Prequalification of ACTs ... Summary of product characteristics ... according to ICH Q7A:

Pharmaceutical Standards for Artemisinin and its derivatives

Requirements for Prequalification of ACTs

Artemisinin Forum 2008Guilin, China

Maryam MEHMANDOUST, PhDPrequalification of Medicines Programme

QSM / EMP/ HSS

Pharmaceutical Standards for Artemisinin and its derivatives. Requirements for Prequalifiaction of ACTs, Guilin, China, November 2008- Maryam MEHMANDOUST

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GlossaryGlossaryAPI Active Pharmaceutical Ingredient (interchangeable with drug substance or active substance)

APIMF Active Pharmaceutical Ingredient Master File

ARV Antiretroviral

CoS (CEP) Certificate of Suitability

CRO Contract Research Organisation

EDQM European Directorate for Quality of Medicines and HealthCare

EoI Expression of Interest

FPP Finished Pharmaceutical Product

GCP Good Clinical Practices

GLP Good Laboratory practices

GMP Good Manufacturing Practices

ICH International Conference on Harmonization

Ph. Int. International Pharmacopoeia

JP Japanese Pharmacopoeia

Ph. Eur. European Pharmacopoeia

PQ Prequalification

RH Reproductive Health

SM of the API Starting material of the API

SPC Summary of Product Characteristics

TB Tuberculosis

USP United States Pharmacopoeia


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UN / WHO Prequalification Programme for Medicines

UN / WHO Prequalification Programme for Medicines

Action plan of UN since 2001 aiming to facilitate access to priority medicinal products

Revision of the procedure in October 2008

– Categories: HIV/AIDS, Malaria, Tuberculosis, Reproductive Health, Influenza

– Potentially other categories of products possible, if there is the need

– To ensure quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID)

– Products meeting WHO recommended Quality Standards to be included in the list of Prequalified products

– Inclusion in the list does imply any approval by WHO of the products and manufacturing sites- this is the sole prerogative of National Authorities


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Prequalification Programme for MedicinesPrinciples of Quality assessment procedure

Prequalification Programme for MedicinesPrinciples of Quality assessment procedure

General understanding of the production and quality control activities of the manufacturer

Assessment of product data and information on safety, efficacy and quality

Assessment of manufacturing sites for consistency in production, quality control of starting materials and FPPS through compliance with GMP

Assessment of clinical testing units or CROs for compliance with GCP and and GLP

Reliance on the information supplied by national DRAs

Random sampling and testing

Handling of complaints and recalls

Monitoring of complaints from agencies and countries


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Prequalification Programme for MedicinesHow does it work?

Prequalification Programme for MedicinesHow does it work?

Compliance

Correctiveactions

Compliance

Assessment Inspections

PrequalificationListing

Maintenance and monitoring

Product dossierSMF

Expressionof Interest

Response to questions


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Prequalification Programme for MedicinesMaintenance of Prequalification Status

Prequalification Programme for MedicinesMaintenance of Prequalification Status

Several ComponentsReporting of variations

• To demonstrate that intended or implemented changes have no negative impact on safety and efficacy of the Prequalified product

Random sampling and testing of prequalified products, investigation if failure to meet the approved criteria

Investigation of complaints on prequalified products communicated to WHO

• Report of the investigation available to the applicant/manufacturer and the concerned DRA

Re-evaluation of the products and manufacturing sites including re-inspection of Mfg sites and clinical testing units at least once every 5 years

Risk-based approach e.g. information received from the stringent authorities


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Prequalification Programme for MedicinesCharacteristics of the prequalified products to be made available for

public access at the WHO website

Prequalification Programme for MedicinesCharacteristics of the prequalified products to be made available for

public access at the WHO website1. Product WHO reference number

2. International Nonproprietary Name (INN) of active ingredient(s)

3. Dosage form and strength

4. Trade name(s) of the product (if applicable)

5. Name of applicant and official address

6. Name of manufacturer of finished product, physical address of manufacturing site(s)

(and unit, if applicable)

7. Name of API manufacturer, physical address of manufacturing site(s) (and unit, if

applicable)

8. Product description (as in finished product specifications, i.e. coated, scored, etc.)

9. Pack size(s), primary and secondary packaging material(s)

10. Storage conditions

11. Shelf-life (provisional, if applicable)

12. Summary of product characteristics

13. Package leaflet14. Labelling


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Prequalification Programme for MedicinesACTs in the latest (6th) Expression of Interest

Prequalification Programme for MedicinesACTs in the latest (6th) Expression of Interest


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Prequalification Programme for MedicinesGuidelines for the assessment of product dossiers/quality

Prequalification Programme for MedicinesGuidelines for the assessment of product dossiers/quality

-- Guideline on submission of documentation for prequalification of multi-source (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis (Main Generic guide with 8 annexes) [under revision]

-- Innovators Under revision

-- Supplement 1 : Dissolution testing

- Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable)

- Guidelines for registration of fixed-dose combination medicinal products

- Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure

-- Guidance on variations to a prequalified dossier- will be revised in 2009-2010

-When PQ guidelines are silent, ICH requirements will apply


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Prequalification Programme for MedicinesPrequalification Programme for Medicines

Active Pharmaceutical Ingredient (API)

A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a

therapeutically active compound (ingredient)

Artemisinin is not currently listed in PQ EoI as an API.


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Prequalification Programme for MedicinesArtemisinin and its derivatives in Ph. Int.

Prequalification Programme for MedicinesArtemisinin and its derivatives in Ph. Int.

-- Artemether (listed in PQ EoI)

- Artemisinin described as an API in the Ph. Int., monographs of related capsules and tablets available

- Artemotil (arteether)

- Artenimol (Dihydroartemisinin)

- Artesunate (listed in PQ EoI)


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Prequalification Programme for MedicinesDifficulties in PQ dossiers/quality

Prequalification Programme for MedicinesDifficulties in PQ dossiers/quality

- Information on method of preparation/extraction of artemisininand its quality controls is lacking

- Manufacturing process is fragmented and what is presented in dossiers is usually very short, e.g. one step

- Monographs of the Ph. Int. on artemether and artesunateshould be further clarified e.g. addition of list of impurities Acknowledgment in working document QSM/EC/08.30 of the EC of October 2008 to revise and improve the monographs but first the FPP ones.


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Prequalification Programme for MedicinesRequirements for Prequalification /API section

Prequalification Programme for MedicinesRequirements for Prequalification /API section

Scientific data on the API can be submitted to PQ using following ways and order of preference

-- A valid Certificate of Suitability (CoS) or CEP, issued by EDQM(not applicable to artemisinin derivatives as not described in the Ph. Eur.)

- An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2 and presented in CTD format (see APIMF guideline and separate presentation)

- Complete submission of data requested in Section 2 of PQ product dossier


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Prequalification Programme for MedicinesRequirements and dossier format for APIs

Prequalification Programme for MedicinesRequirements and dossier format for APIs

PQ dossier section 2CTD2.1 Nomenclature

2.2 Properties of API (s)

S.1 General Information - Nomenclature- Structure- General Properties

2.3 Site(s) of Manufacture

2.4 Route(s) of synthesis- API not described in pharmacopoeia- Specifications of raw materials and intermediates used in synthesis- API described in a pharmacopoeia

S.2 Manufacture- Manufacturer- Description of manufacturing process- Control of materials- Control of critical steps and intermediates- Process validation- Manufacturing process developmentS.3 Characterisation- Elucidation of structure- Impurities

2.5 Specifications S.4 Control of Drug Substance

S.5 Reference Standards or Materials 2.6 Container Closure System

2.7 Stability testing

S.6 Container Closure System

S.7 Stability testing


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Prequalification Programme for MedicinesAPI section


3.2.S.1. General InformationNomenclature

- INN or modified INN, - Pharmacopoeial reference if relevant (Ph. Int., USP, Ph. Eur.),- Chemical name (CAS or IUPAC), other chemical names such as USAN or BAN,

- CAS (Chemical Abstracts Service) registry number.

Chemical structure- Structural formula including relative and absolute stereochemistry, - Molecular formula and relative molecular mass - Indication if the API is a racemate or an enantiomerically pure substance or a specific

isomer.E.g. artesunate is obtained only as alpha-epimer (10S) or artemether is predominantly the beta-epimer


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Prequalification Programme for MedicinesAPI Section


3.2.S.1. General InformationGeneral propertiesList properties of the API such as below (relevant for manufacturability and performance of the FPP)

- physical forms (crystalline, amorphous,…),- partition coefficient (oil/water), - hygroscopicity (water uptake at specified ambient temperature), - pH and pKa values, - solubility characteristics (solubility in water at different pH 1.2 to 6.8), - particle size, - polymorphism.

Artemisinin derivatives are either insoluble or slightly insoluble in water, therefore need to address issues of particle size and polymorphism


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3.2.S.2. Manufacture / Manufacturer(s)

Name, address and responsibility of each manufacturer, including contractors, manufacturing and each proposed manufacturing site or facility involved in the

including specific steps such as chain milling or micronization

(if any) with indication of unit, plot, blockActual manufacturing sites Same information as above for alternative sites

GMP compliance certificate for each site of production of API (if available), A valid manufacturing authorization for the production of APIs (PQ requirement)

to the GMP for APIsaccordingperformedbeshouldprocessManufacturingaccording to ICH Q7A: Good manufacturing practice for active pharmaceuticalingredients, Adopted by WHO EC


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3.2.S.2. ManufactureDescription of manufacturing process and process controls

- A flow diagram of the process and a scheme of synthesis- Description of the synthesis should go sufficiently back to well-characterized starting materials- Detailed description of the synthesis step-by-step indicating materials, reagents and solvents used and critical steps identified by the manufacturer- Scale of manufacture: typical batch size and the maximum batch size (the range)- Last step of purification/crystallisation and solvents used should be described

Alternate processes (if any), description with the same level of details than the main process. Attention if change in the impurity profile

Reprocessing and reworking steps should be clearly described (if any) with justification, attention to different impurity profile resulting from reworking


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3.2.S.2. Manufacture, Description of manufacturing process and process controls

β-artemether

α-artesunateconfiguration at 10 should be inversed

Artemisinin DHA


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3.2.S.2. ManufactureStarting material of the APIControl of Materials/

Definition as per ICH Q7A: a raw material, intermediate, or an API that is used in production of an API and that is incorporated as a significant structural fragment into the structure of the API. It can be an article of commerce, purchased from another supplier or manufactured in-house.


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Definition of API starting material as per ICH Q7A should be distinct from the concept of "Starting material for synthesis" used in assessment.It defines the starting point of the synthetic process of an API to be submitted in the dossier

the ICH Q7A "API starting may precedeStarting material for synthesis in the dossier material" by several steps in the synthetic process

-In general, the starting material for synthesis should be a synthetic precursor one or more prior to the final API intermediatesynthetic steps

Pharmaceutical sciences- Questions and answersTherapeutic Products Directorate, Health Canada


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Provide brief outline of the preparation of the starting material of the API beginning from simpler molecules including solvents and reagents in order to enable assessors to judge of the appropriateness of specifications of the starting material of the API.CPMP/QWP/130/96, Rev 1 (December 2003)


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3.2.S.2. ManufactureStarting material of the API should be qualifiedMaterials/ Control of

) (smanufacturerName and address (manufacturing site) of the starting material -- If several sources, indication of differences in the mode of preparation- If differences, then specifications should cover the quality of material sourced from all suppliers

Starting material of the API should be well characterized, structure well defined.Specifications proposed for the starting material as a minimum: identification, related substances, assay and sometimes residual solvent and catalystsFor artemisinin as SM of atemether or artesunate, it is not obligatory that it complies with the limits of the Ph. Int. but the specifications should be appropriate for the intended use.

If the route of synthesis too short i.e. 1 step and the starting material is pharmacopoeial, full compliance with its monograph should be shown by evaluation of its quality.


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3.2.S.2. ManufactureControl of Materials

Specifications for solvents and reagentsICH class I solvents such as benzene should be avoided

- Solvents used in final stages require greater purity and control - Control of residual benzene in solvents such as toluene

Recovered solvents: specifications and useQuantitative and qualitative composition of denatured solvents

Recovered materials: description of recovery, specifications and use

Any material used in the process which may be of biological origin, viral and/or TSE safety aspects should be addressed. Declaration on use/non use of material of biological origin.


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3.2.S.2. ManufactureControls of critical steps and Intermediates

intermediates: as a minimum identification, related isolatedSpecifications for -substances and assay testing.

- In-process controls

-Identification of critical steps (examples)-. Where significant impurities are introduced or removed

. Where an essential structural element is introduced e.g. a chiral center-. Where a major chemical transformation is performed

-. Step having an impact on solid state properties or homogenity of the API


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3.2.S.2. Manufacture

Process validation and/or evaluation- Validation of critical steps identified- Validation of aseptic processing and/or sterilization

Manufacturing Process Development- Significant changes made to the manufacturing process and/or site during development of the process and scale-up


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3.2.S.3. CharacterisationElucidation of structure and other characteristics

Confirmation of structure based on synthetic route and spectral analyses

Pharmacopoeial APIs: comparison of spectral data between the pharmacopoeial reference standard and the test product

Non pharmacopoeial API :evidence of structure should be brought by elemental analysis, IR, NMR (proton and carbon), UV, mass with interpretation of spectra, X-ray and so on.- Unequivocal proof of configuration of chiral centres (if applicable) and geometric isomerism (if applicable) e.g. by single X-ray crystal


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3.2.S.3. Characterisation/ ImpuritiesDiscussion on potential and actual impurities

theirfor alsoaspects but chemicaltheirfor onlynot consideredbeare to Impuritiesaspects (qualification)safety

- Organic impuritiesBy-productsStarting materials and / or intermediates not reactedImpurities contained in starting materialsDegradation products of the APIReagents, catalysts

- Residual solvents (PQ refers to ICH Q3C)- Inorganic impurities (reagents, heavy metals, inorganic salts, metal catalysts)


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Prequalification Programme for MedicinesImpurities artemisinin derivatives


3.2.S.3. Characterisation/ Impurities

Impurities contained in the starting material - ArtemisininBiosynthetic by-products: Starting materials from vegetable origin should be fully characterized and a contaminant profile should be established and submitted.Arteannuin , Artemisitine, Artemisinic acid,

Cultivation reagentsPesticide residues (Ph . Eur. 2.8.13.), fumigants, mycotoxins

Solvents from the extraction processHexane, benzene, acetonitrile, ether, pentane, chloroforme, etc….In any case ICH Q3C (R) will apply.


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By-products, starting materials or intermediates not reacted. Artemisinin. Dihydroartemisinin (starting material for derivatives). α-Arthemether, α-Artheether. β-Artesunate.

Reagents, catalysts, residual solvents from the chemical transformationMethanol, acetonitrile, chloroforme, acetone …Boron residues, succinic acid/anhydride, triethylamine, dimethylaminopyridine, other bases

Degradants- Product obtained by openinng of the endoperoxide leading to loss of antimalarial activity, - Product after loss of succinic moiety known as glycan


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Prequalification Programme for MedicinesPh. Int. Monograph limitations



Artemether related substances example

No impurity more than 0.5%, only one impurity between 0.25% and 0.5%, any other impurity NMT 0.25%, total of impurities NMT 1%.No list of impurities at the end of monograph

Some manufacturers only report one figure between 0.25% and 0.5% and one figure below 0.25%. Not at all clear what is there: artemisinin, DHA, alpha artemether or other impurities which can be unknown?


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- It should be clarified each time what impurities are known such as artemisinin, DHA, …

-- All the results are to be provided from the disregard limit of the monograph (usually 0.05%)

-impuritiesunknown recurrentIt should be clarified if there are

-If important levels are found, attempts should be made to characterise them or to reduce them

-Absolute need for more collaboration between manufacturers of artemisininderivatives and Ph. Int. to improve these monographs


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For non pharmacopoeial APIs, impurities should be either identified and qualified IF NOT

ICH Q3A thresholds of identification and qualification apply

Maximum Daily Dose

Reporting Threshold

Identification Threshold

Qualification Threshold

≤ 2g/day 0.05% 0.10% or 1mg per day intake (whichever is lower)

0.15% or 1mg per day intake (whichever is lower)

≥ 2g/day 0.03% 0.05% 0.05%


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3.2.S.4. Control of the APISpecifications for NON Pharmacopoeial substancesICH Q6A apply

Specifications for Pharmacopoeial substancesRecognised Pharmacopoeias by Prequalification: Ph. Int., USP, Ph. Eur., BP

The claimed pharmacopoeia by the applicant should be specified

The current monograph in force in the claimed pharmacopoeia always applicable BUT use of in-house method acceptable provided to be superior

Complete by additional specifications not included in the monograph- Residual solvents (specific to each process)- Polymorph and particle size (where applicable e.g. poorly soluble drugs)- Sterility or microbial contamination,…(where applicable)


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3.2.S.4. Control of the APIAnalytical procedures/ Pharmacopoeial APIs

Any non pharmacopoeial method should be described in detail to be replicated by a Control Laboratory

Validation of analytical proceduresFor pharmacopoeial methods, the applicability of the method to the manufacturer's equipment should be shown: SST, specificity, …

The pharmacopoeial related substances method should be always shown suitable to determine impurities related to the manufacturer's specific route of synthesis

If monograph available but in-house method chosen, it should be shown that the in-house methods is superior or at least equivalent to that of the monographNon pharmacopoeial methods should be fully validated


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3.2.S.4. Control of the APIBatch analyses

Description of the batches: batch number, size, site and date of manufacturing, use of the batch e.g.

each source of API and each siteprimary batches from 2Results of at least Primary batches should be at least of pilot size

For quantitative tests, actual numerical results should be given.Statements such as "complies" are not acceptable.

Justification of specifications- inclusion OR omission of certain main/ critical tests and acceptance criteria, - any modification of pharmacopoeial tests.

- Specifications of non pharmacopoeial APIs justified as per ICH Q6


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3.2.S.5. Reference Standard or MaterialsFor pharmacopoeial APIs: use an official Reference Standard.Working standard should be qualified against the official RS

For non-pharmacopoeial APIsA primary and/or a working standard are to be established with description of how ithas been set in terms of identity and assay

3.2.S.6. Container Closure system- Description of the bulk storage container / primary packaging- Identification of materials and their specifications- Choice of material to be justified: compatibility of the API with materials of the container. by stability results obtained. protection from moisture and light (if applicable). sorption, leaching to be studied mainly in case of liquid APIs


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3.2.S.7. Stability testing

Forced degradation studies in stress condition

- Help to know about the intrinsic stability of the API

- Help to know about the degradation pathways and degradation products formed

- Help to know whether the analytical method is suitable to determine degradationindicating-stabilityisitwhether/ and products

if the testingstress performnot to possible isit, APIexistingFor an information can be found in literature or included in transparency list of Ph. Monograph, not possible for artemisinin derivatives because of lack of list of impurities


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3.2.S.7. Stability testing

Regulatory stability testingserves to define a re-test period for the APIto recommend a storage condition

Definition of re-test periodPeriod of time during which the API is expected to remain within its specifications and can be used in the manufacture of a given product (without control prior to manufacture of Drug Product) in condition that the API has been stored under defined conditions

If the re-test period not defined, The API is to be tested before manufacture of each lot of drug product


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3.2.S.7. Stability testingRe-test period of the API

- Selection of batches (at least 3 pilot)- Same packaging than that proposed for commerce /distribution- Parameters to be testedThose susceptible to change during storage and affecting quality and safety: assay, impurities, isomeric nature…

-Analytical methods (should be the same at release OR if different validatedand demonstrated to be stability indicative)


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3.2.S.7. Stability testingRe-test period of the API

Storage conditions (ICH general case): long term, intermediate, accelerated

The long term storage condition should go with real climatic conditionse.g. Zone IVb: long term is 30%C / 75% RHZone IVa: long term is 30%C / 65% RHNEW WHO guideline on stability adopted by the EC in October 2008

Extrapolation: possible either according to PQ supplement 2 (not applicable to artemisinin derivatives) or according to ICH Q1E

Stability study should be continued to cover the re-test period accorded


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Prequalification Programme for MedicinesFPP Section

Prequalification Programme for MedicinesFPP Section

- Manufacturing and marketing authorization- Pharmaceutical development- Formulation- Sites of manufacture- Manufacturing process- Manufacturing process controls of Critical steps and intermediates- Process validation and Evaluation- Specifications for excipients- Control of the FPP- Container/closure system (s) and other packaging- Stability testing- Labelling- SPC- PIL


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Thank you for your attention

Documents

Pharmaceutical Standards for Artemisinin and its ... · its derivatives Requirements for Prequalification of ACTs ... Summary of product characteristics ... according to ICH Q7A: